Metallothioneins (MTs) are ubiquitous low molecular weight proteins and polypeptides of extremely high metal and cysteine content which give rise to metal-thiolate clusters. The MT gene family consists of four subfamilies designated MT1 through MT4. Increasing evidence shows that mammalian MT1/MT2 isoforms are involved in zinc homeostasis and protection against heavy metal toxicity and oxidative stress. MT3 is expressed mainly in neurons but also in glia; MT4 is mostly present in differentiating stratified squamous epithelial cells.
Vallee and Margoshe disclosed MT from purification of a Cd-binding protein from horse (equine) renal cortex. (Margoshes & Vallee, “A cadmium protein from equine kidney cortex”. Journal of the American Chemical Society 79 (17): 4813-4814, 1957) There are four main isoforms expressed in humans (family 1, see chart below): MT1 (subtypes A, B, E, F, G, H, L, M, X), MT2, MT3, MT4. The different isoforms of MTs are found in different tissues in mammalians. For example, MT1 and MT2 are generally found in all organs, MT4 is mainly expressed in stratified tissues, but MT3 predominately exists in brain. MT3, which is also named growth inhibitory factor (GIF).
MTs play an important role in transcription factor regulation, thus malignant transformation of cells and ultimately cancer would be caused by the problems with MT function or expression. (Krizkova et al., “Metallothionein—a promising tool for cancer diagnostics”. Bratisl Lek Listy 110 (2): 93-7, 2009.) It was found that the expression of MTs increased in some cancers of the breast, colon, kidney, liver, skin (melanoma), lung, nasopharynx, ovary, prostate, mouth, salivary gland, testes, thyroid and urinary bladder; and MT expression decreased in hepatocellular carcinoma and liver adenocarcinoma. (Cherian, “Metallothioneins in human tumors and potential roles in carcinogenesis”. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 533: 201-209, 2003.)
Heavy metal toxicity has been proposed as a hypothetical etiology of autism, and dysfunction of MT synthesis. However, MT dysfunction has not specifically been linked to autistic spectrum disorders. It was reported in a study investigating children exposed to the vaccine preservative thiomersal in 2006 that levels of MT and antibodies to MT in autistic children did not differ significantly from non-autistic children. (Singh & Hanson, “Assessment of metallothionein and antibodies to metallothionein in normal and autistic children having exposure to vaccine-derived thimerosal”. Pediatr Allergy Immunol 17 (4): 291-6, 2006.)
Accordingly, it is desirable to develop new fusion proteins related to metallothioneins that satisfy a need in the art by providing new diagnostic or therapeutic agents.